The present invention relates to the field of pharmacology, and particularly to derivatives of N-phenylanthranilic acid and/or 2-benzimidazolone for the treatment of pathologies, especially pathologies related to potassium ion flux through voltage-dependent potassium channels and/or cortical and peripheral neuron activity.
Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels are present in all animal cells and affect such processes as nerve transmission, muscle contraction, sensation processing and cellular secretion. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands and ATP-sensitivity.
Potassium channels have now been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport. Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities [Wei et al., Neuropharmacology 35(7): 805-829 (1997)]. Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage. Two other families, CNG and SK/IK, also contain this motif but are gated by cyclic nucleotides and calcium, respectively. The three other families of potassium channel alpha subunits have distinct patterns of transmembrane domains. Slo family potassium channels, or BK channels have seven transmembrane domains [Meera et al., Proc. Natl. Acad. Sci. U.S.A. 94(25): 14066-71 (1997)] and are gated by both voltage and calcium or pH [Schreiber et al., J. Biol. Chem. 273: 3509-16 (1998)]. Another family, the inward rectifier potassium channels (Kir), belongs to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or “two-pore”) contains two tandem repeats of this inward rectifier motif.
Potassium channels are typically formed by four alpha subunits, and can be homomeric (made of identical alpha subunits) or heteromeric (made of two or more distinct types of alpha subunits). In addition, potassium channels made from Kv, KQT and Slo or BK subunits have often been found to contain additional, structurally distinct auxiliary, or beta, subunits. These subunits do not form potassium channels themselves, but instead they act as auxiliary subunits to modify the functional properties of channels formed by alpha subunits. For example, the Kv beta subunits are cytoplasmic and are known to increase the surface expression of Kv channels and/or modify inactivation kinetics of the channel [Heinemann et al., J. Physiol. 493: 625-633 (1996); Shi et al., Neuron 16(4): 843-852 (1996)]). In another example, the KQT family beta subunit, minK, primarily changes activation kinetics [Sanguinetti et al., Nature 384: 80-83 (1996)].
Slo or BK potassium channels are large conductance potassium channels found in a wide variety of tissues, both in the central nervous system and periphery. They play a key role in the regulation of processes such as neuronal integration, muscular contraction and hormone secretion. They may also be involved in processes such as lymphocyte differentiation and cell proliferation, spermatocyte differentiation and sperm motility. Three alpha subunits of the Slo family have been cloned, i.e., Slo1, Slo2, and Slo3 [Butler et al., Science 261: 221-224 (1993); Schreiber et al., J. Biol. Chem., 273: 3509-16 (1998); and Joiner et al., Nature Neurosci. 1: 462-469 (1998)]. These Slo family members have been shown to be voltage and/or calcium gated, and/or regulated by intracellular pH.
Certain members of the Kv family of potassium channels were recently renamed [see, Biervert, et al., Science 279: 403-406 (1998)]. KvLQT1 was re-named KCNQ1, and the KvLQT1-related channels (KvLR1 and KvLR2) were renamed KCNQ2 and KCNQ3, respectively. More recently, additional members of the KCNQ subfamily were identified. For example, KCNQ4 was identified as a channel expressed in sensory outer hair cells [Kubisch, et al., Cell 96(3): 437-446 (1999)]). KCNQ5 [Kananura et al., Neuroreport 11(9): 2063 (2000)], KCNQ2/3 [Main et al., Mol. Pharmacol. 58: 253-62 (2000)], KCNQ3/5 [Wickenden et al., Br. J. Pharma 132: 381 (2001)] and KCNQ6 have also recently been described.
KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassium channels associated with benign familial neonatal convulsions (“BFNC”), a class of idiopathic generalized epilepsy [see, Leppert, et al., Nature 337: 647-648 (1989)]. These channels have been linked to M-current channels [see, Wang, et al., Science 282: 1890-1893 (1998)]. The discovery and characterization of these channels and currents provides useful insights into how these voltage dependent (Kv) potassium channels function in different environments, and how they respond to various activation mechanisms. Thus, for example, it was recently found that KCNQ2 and KCNQ3 α subunits are expressed in sensory dorsal root ganglion (DRG) neurons which are involved in nociceptive signaling pathways (Passmore et al., 23(18): 7227-36, 2003). Such information has now led to the identification of modulators of KCNQ2 and KCNQ3 potassium channels or the M-current, and the use of such modulators as therapeutic agents.
A potassium channel opener that has gained much attention is retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester). Retigabine was first described in European Patent No. 554,543. Compounds related to retigabine have also been proposed for use as potassium channel modulators, see for example U.S. patent application Ser. No. 10/022,579.
Retigabine is highly selective for potassium channels consisting of the subunits KCNQ2 and KCNQ3. In addition, retigabine activates the homomultimerous channel, which contains only the subunit KCNQ2. Only marginal voltage-dependent currents are measurable in cells, which express only the homomeric channel from the KCNQ3 subunit (see, U.S. Pat. No. 6,472,165).
U.S. patent application Ser. No. 10/075,521 teaches 2,4-disubstituted pyrimidine-5-carboxamide derivatives as KCNQ potassium channel modulators.
U.S. patent application Ser. No. 10/160,582 teaches cinnamide derivatives as KCNQ potassium channel modulators.
U.S. Pat. No. 5,565,483 and U.S. patent application Ser. Nos. 10/312,123, 10/075,703 and 10/075,522 teach 3-substituted oxindole derivatives as KCNQ potassium channel modulators.
U.S. Pat. No. 5,384,330 teaches 1,2,4-triamino-benzene derivatives as KCNQ potassium channel modulators.
U.S. Pat. No. 6,593,349 teaches bisarylamines derivatives as KCNQ potassium channel modulators. The two aryl groups of the compounds taught in U.S. Pat. No. 6,593,349 are a pyridine derivative and a five-membered heterocyclic compound.
A significant disadvantage of the KCNQ potassium channel modulators known in the art is that these are generally difficult to prepare, requiring complex multi-step syntheses and that in some cases these modulators are non-specific or even toxic.
There is, hence, a widely recognized need for, and it would be highly advantageous to have new and effective potassium channel modulators devoid of the above limitations.